Pruritus (itching) is a sensation peculiar to the skin, mucous membrane and cornea and a symptom that we feel in our daily life. It is a symptom that is most frequently felt painful in skin diseases accompanying inflammation. Diseases associated with itching include visceral diseases such as renal disease (chronic renal failure), hepatic disease, diabetes, malignant tumor and the like in addition to those caused by skin diseases such as urticaria, atopic dermatitis and the like. Different from peripheral itching caused by skin diseases, itching caused by visceral diseases is a central itching involving the opioid system (endogenous opioid and opioid receptor) and is clinically refractory. When this central itching becomes severe, the scratching behavior and annoyed feeling increase to a level preventing staying still, which in turn disturbs everyday life and causes sleep disorder, etc., thereby markedly lowering the QOL (Quality of Life) of patients. As a therapeutic drug for such central itching, nalfurafine is attracting attention in recent years.
Nalfurafine is an opioid K (kappa) receptor agonist, a drug that inherently shows an antipruritic effect on central itching involving the opioid system. At present, as a nalfurafine-containing pharmaceutical product, an oral preparation Remitch capsule 2.5 μg (Torii Pharmaceutical Co., Ltd.) is on the market.
Oral administration is the most common method of administering drugs and is generally regarded as the first choice since it is superior in terms of QOL of patients. However, it may cause a transient increase in the blood drug concentration and expression of strong side effects. In addition, since drug supply is not sustainable, the effective blood concentration cannot be maintained for a long time and sustainability of the effect sometimes becomes insufficient.
Indeed, nalfurafine oral preparations show a dose-dependent increase in the expression rate of side effects such as insomnia, constipation, drowsiness and the like, which suggests a possibility that a transient increase in the blood nalfurafine concentration causes expression of side effects. Also, a decrease in the blood nalfurafine concentration and attenuation of antipruritic effect were observed within 24 hours after a single administration.
Therefore, the development of a nalfurafine-containing preparation that suppresses a transient increase in the blood drug concentration causing side effects, and can maintain the blood drug concentration constant for a long time has been desired.
As a preparation that can suppress a transient increase in the blood drug concentration and maintain blood drug concentration constant for a long time, a percutaneous absorption patch is available. Percutaneous absorption patches were generally developed on the premise that they are applied to normal skin without trauma, dermatitis and the like. This aims to suppress permeation of a drug through the skin by the skin barrier function of the horny cell layer and the like, thereby preventing easy occurrence of a transient increase in the blood drug concentration (patent document 1).
However, in patients with severe pruritus to which nalfurafine is applied, they often scratch the whole body and damage the horny cell layer and the like, thus sometimes producing a wide area where skin barrier function is insufficient. When a percutaneous absorption patch containing nalfurafine is applied to such patients, the skin barrier function is not sufficiently exhibited and an excess amount of nalfurafine permeates through the skin in a short time. As a result, there is a risk of causing a transient increase in the blood nalfurafine concentration. Generally, the risk of causing a transient increase in the blood drug concentration can be avoided by lowering the drug concentration of the percutaneous absorption patch. In this case, it is possible that the decrease in the drug concentration of the patch causes failure to maintain a given drug skin permeation amount and makes it difficult to supply the drug into the blood for a long time. At the present stage, no technology has been developed that solves these two problems at the same time.
Thus, the development a nalfurafine-containing percutaneous absorption patch capable of maintaining a given level of drug skin permeation amount without permeation of an excess amount of the drug through the skin in a short time even when applied to the skin in which the horny cell layer and the like are damaged and the skin barrier function is insufficient has been demanded.